Domestic cats with genetic Gm2 gangliosidosis will be used as an animal model for the study of enzyme replacement in vivo, and for the development of rational and effective therapeutic methodolgies applicable to treatment of the human lipidoses, Tay-Sachs- and Sandhoff disease. This research is focused on two major problems of enzyme replacement in the neurolipidoses: preferential hepatic uptake of, and blood-brain barrier (BBB) impermeability to exogenous lysosomal enzymes. In order to obtain an enzyme form which escapes preferential hepatic uptake, the effects of carbohydrate chain modifications of purified human placental beta-hexosaminidase on its organ disposition and endocellular survival will be assessed in normal animals. Beta-hexosaminidase from other sources (plasma, I-cell disease fibroblast culture fluids) will also be studied. The kinetics of hepatic binding will be studied in vitro using liver plasma membrane preparations. Controlled cerebral gas microembolism will be used to induce BBB permeability and, in combination with inhibition of hepatic uptake, to deliver exogenous beta-hexosaminidase to the feline central nervous system. Biochemical and ultrastructural mechanisms underlying induced BBB permeability will be explored. Neuronal uptake of the enzyme will be studied in vivo and in short term cultures of cells isolated from the animals' brain. Prevention of possible neurologic complications of cerebral gas embolism by means of hyperbaric treatment will be explored. The effect of these methodologies on central nervous system storage of Gm2 ganglioside and of hepatic and extrahepatic storage of neutral glycolipid will be determined in affected animals.